Metabolism and Drug Interactions

Absorption and Bioavailability

drug present in intestinal lumen after absorptions and will use transcellular and paracellular pathways to be bypass the wall into the liver.

It will experience first pass effect where drug is metabolised and excreted, drug molecules that are not metabolised enter the systemic circulation where plasma protein binding happens and travels to action site.

Metabolism

  • metabolism is biotransformation

  • it is an enzymatic process where it converts non polar lipophilic compounds into more polar hydrophilic compounds to be excreted in urine.

  • metabolism of drugs into hydrophilic metabolites is needed to eliminate compounds from body - whether its harmful or not

  • helps to detoxify, active prodrugs and facilitate drug clearance

  • organs like liver, kidneys, lung, intestines and skin help with clearance;

drugs excreted through skin usually as sweat or breastmilk. Non soluble molecules are broken down into soluble molecules to be passed through → soluble is best for excretion as it dissolves in water

The liver

  • major organ of drug/toxin metabolism

  • lipid soluble drugs enter hepatocytes and reach enzymes for metabolism

  • water soluble drugs do not enter and are excreted instead

there are 2 phases

  • phase 1 reactions where drug is made more polar or more reactive using modifications like reduction, oxidation and hydroxylation to prepare drugs for phase 2

  • phase reactions are conjugation reactions where large polar groups make the drug more water soluble by adding a functional group for greater excretion like glucuronidation, acetylation etc.

phase 1 reactions:

  • converts drug into more polar metabolite by introducing or bringing a functional group like OH, NH2 OR SH.

  • usually through reduction, oxidation and hydroxylation where catalysed by cytochome p450

  • usually loss of pharmacological activity where metabolite may be equally or more active than prodrug or toxic metabolite

  • metabolites are what enzymes convert drugs into → they can inactive, less active or more active which also determines if its toxic.

  • metabolites are generally active or less active with exceptions like ramipril and losartan

  • prodrugs are pharmacologically inactive or has low activity - converted rapidly to activate usually by hydrolysis of ester or amide → this will maximise amount of molecules to reach site of action (increasing bioavailability)

  • e.g., valacyclovir (prodrug) is used to improve carrier mediated transport - transported across intestinal epithelial cell membranes by transporters and then enzymatically hydrolysed to acyclovir before turning into its active form acyclovir triphosphate in the cells where it will finally work its therapy

phase 2 reactions:

  • covalent links are formed between functional groups on parent compound of phase 1 metabolite and an endogenous substrate.

  • conjugation reactions like sulfation and acetylation

  • resulting compound is now highly polar so it is rapidly excreted in urine and faeces.

cytochrome p450

  • phase 1 metabolite enzyme

  • has iron with copper which is then oxidised to have peak 450

  • can metabolise a wide range of drugs

  • number after root prefix = family

  • letter after family = subfamily

  • number after letter - individual enzyme

  • asterisk and number after number identifies the specific allele or variant

cyp families are numbered from CYP1 to CYP51 with most common being CYP3A4 and CYP2D6 → involved in drug metabolism, steroid synthesis and other biological processes. in this case only focus on drug metabolism.

patients with liver abnormalities may have less metabolism so drugs that need to be given will have a lower dosage so a toxic concentration doesn’t build up in blood. If a prodrug is to be given then dose is increased instead so it can be activated in liver - as its already inactive there wont be a toxic accumulation until it is activated which would have been passed through anyways → this gives a sustained release effect as it requires a longer reaction time to get desired therapy. Those with kidney issues, dosage is lowered to compensate for accumulation in urine as only 1 working kidney is present → will not be able to handle the extra pressure.

when the phase reactions happen, it is not infinite where you will get abundance of conjugate. This will only build up to a certain concentration until there is overdose of drug and derivative which wont pass through urine

First pass elimination

  • through the liver to metabolise and eliminate drug before it reaches systemic circulation

  • only happens when drug is inactive/metabolised in GIT, gut wall or liver before reaching systemic circulation

  • leads to reduced drug concentration at site of action

  • most commonly for oral drugs

  • to combat this - use of IV so it doesn’t go through liver but is directly passed into systemic circulation to action site.

Factors affecting drug metabolism

food/drug interactions

predicts whether a drug is inducing (enzyme activity increases therefore metabolism increases) or if a drug is inhibiting (decrease in enzyme activity and metabolism), some may even cause adverse effects

drug-drug interactions:

  • how one drug affects the metabolism of another drug

  • if 2 drugs that are metabolised by same cytochrome p450 then dosage needs to be checked and amended as they would compete for the same enzyme

  • one drug can induce anothers enzyme activity which would increase metabolism and is not a desired effect so needs to adjusted

  • Drug A can increase metabolism for Drug B then drug B needs to have a higher dose to get desired effects as drug A would increase drug Bs metabolism.

  • if it is a prodrug - it could be activated from inducer and dosage must be lowered instead.

grapefruit juice:

  • inhibits CYP3A4 and delays elimination so there is increased nephrotoxicity.

  • it can increase plama conc of many drugs

  • reduces plasma conc for aliskiren and biastine as it decreases bioavailability by 30%

  • it also inhibits duodenal enzymes

age

  • children have smaller and underdeveloped livers so their ability to metabolise is lower → liver is also vulnerable to damage

  • elderly have a reduced liver size, hepatic blood flow and enzyme activity so metabolism is lowered too. this could be due to multitherapy or reduction of CYP3A

genetics

genetic polymorphisms explains the different forms and expression of genes and how they are translated into proteins which also express our different phenotypes.

medication can be tailored to patients depending on their genetic polymorphism but this is costly, patients may not want to or it needs extensive justification to undergo the process.

genetic differences can affect how drugs are metabolised - especially across species. variations in genes encoding phase 1 and 2 enzymes lead to different metaboliser phenotypes

paracetamol:

metabolised by conjugation with glucuronic acid (45-55%), sulfuric acid (20-30%) and less than 15% is oxidised to form NAPQI which is toxic - detoxified with conjugation with glutathione.

if toxic amount is achieved - NAPQI increases and outweighs the amount of glutathione is available so there is accumulation with no excretion = hepatic failure and renal tubular necrosis

NAPQI is high reactive and dangerous causing liver damage.

alcohol

chronic alcohol consumption can exacerbate hepatotoxic effects of paracetamol by increasing NAPQI through induction of CYP2E1

liver uses enzymes like ADH and CP450 to metabolise alcohol and drugs - alcohol would compete for these enzymes and slow metabolism down. alcohol is instead metabolised into acetaldehyde which can accumulate and damage liver cells and impair function

Questions:

Single Best Answer (SBA) Questions

Question 1

The primary purpose of drug metabolism (biotransformation) is to:

a) Activate prodrugs to their therapeutic form.

b) Convert lipid-soluble drugs into more water-soluble metabolites for excretion.

c) Facilitate the transport of drugs across the gut wall.

d) Increase the drug's concentration at its site of action.

Answer:

b) Convert lipid-soluble drugs into more water-soluble metabolites for excretion.

This is the fundamental goal of metabolism. While activation of prodrugs (a) is one function, it is not the primary purpose for most drugs. The core aim is to make drugs more hydrophilic to facilitate renal or biliary elimination.

Question 2

A patient with severe cirrhosis (liver failure) is prescribed a medication that is a prodrug. Compared to a patient with normal liver function, what is the most likely required dosage adjustment?

a) The dose should be increased to ensure sufficient active drug is generated.

b) The dose should be decreased to avoid accumulation of the inactive prodrug.

c) The dose should be decreased because the active metabolite will accumulate to toxic levels.

d) No dose adjustment is necessary as the prodrug is inactive.

Answer:

a) The dose should be increased to ensure sufficient active drug is generated.

Your notes correctly state: "If a prodrug is to be given then dose is increased instead so it can be activated in liver." A failing liver has reduced metabolic capacity, so it may not efficiently convert the prodrug into its active form, potentially leading to a subtherapeutic response.

Question 3

Grapefruit juice is known to cause significant drug interactions primarily because it:

a) Induces the activity of the CYP3A4 enzyme, increasing drug metabolism.

b) Inhibits the CYP3A4 enzyme in the liver and gut, increasing bioavailability of some drugs.

c) Binds to drugs in the stomach, preventing their absorption.

d) Competes with drugs for renal tubular secretion.

Answer:

b) Inhibits the CYP3A4 enzyme in the liver and gut, increasing bioavailability of some drugs.

Your notes are correct on this point. Grapefruit juice is a potent inhibitor of CYP3A4, leading to reduced first-pass metabolism and higher systemic concentrations of drugs that are substrates for this enzyme.

Question 4.

In the metabolism of paracetamol, the toxic metabolite NAPQI is normally:

a) The primary product of glucuronidation.

b) Conjugated with glutathione to form a non-toxic compound.

c) Accumulated in patients with a deficiency in sulfuric acid conjugation.

d) Responsible for the drug's analgesic effect.

Answer:

b) Conjugated with glutathione to form a non-toxic compound.

Your notes accurately describe this pathway. At therapeutic doses, the small amount of NAPQI formed is safely detoxified by conjugation with glutathione. Toxicity occurs with overdose when glutathione stores are depleted.

Extended Matching Questions (EMQ)

Questions 5-7:

For each drug metabolism scenario, select the MOST accurate description.

Options:

A. Phase 1 Reaction

B. Phase 2 Reaction

C. First-Pass Metabolism

D. Prodrug Activation

E. Enzyme Induction

Question 5.

Losartan is converted into its active metabolite, E-3174, which is more potent than the parent drug.

Answer:

A. Phase 1 Reaction

This is a classic example of a Phase 1 reaction (oxidation) creating a more active metabolite, as mentioned in your notes.

Question 6.

A glucuronic acid molecule is added to morphine, forming morphine-6-glucuronide, a metabolite that is more potent but also more water-soluble.

Answer:

B. Phase 2 Reaction

This is glucuronidation, a primary Phase 2 conjugation reaction. Your notes state Phase 2 makes compounds "highly polar," but it's important to know that metabolites can sometimes retain or even have increased activity.

Question 7.

The reason the oral dose of morphine is much higher than the intravenous dose to achieve the same analgesic effect.

Answer:

C. First-Pass Metabolism

This is the definitive example of first-pass metabolism. A significant portion of orally administered morphine is metabolized in the liver and gut wall before it can reach the systemic circulation.

Clinical Scenarios (OSCE/Patient Style)

Scenario 1: The Patient on Multiple Medications

Patient: "I've been feeling really unwell and dizzy since I started this new antibiotic a few days ago. I'm also on my usual blood thinner. The doctor knows all my medicines."

As the pharmacist, what is your immediate suspicion and what actions do you take?

* Hypothesize: "That's concerning. Dizziness can be a sign of low blood pressure or other issues. It's possible the new antibiotic is interacting with your blood thinner, potentially increasing its level in your blood and raising the risk of bleeding. Several antibiotics are known to inhibit liver enzymes that metabolise blood thinners like warfarin."

* Gather Information: "To help me look into this, could you tell me the names of the antibiotic and the blood thinner you are taking?"

* Act and Advise: "Based on what you've told me, you should speak to your GP or pharmacist today. Do not simply stop your medications. They may need to check a blood test to see if your blood is too thin and adjust the dose. In the future, it's always a good idea to ask about potential interactions when a new medicine is prescribed."

Scenario 2: Counselling on Paracetamol and Alcohol

Patient: "I'm picking up my co-codamol prescription. I have a bit of a bad back, so I like to have a few whiskies in the evening to help me relax. That's fine, right?"

How do you counsel this patient?

* Provide a Clear Warning: "Thank you for telling me. It's really important you know that combining paracetamol (which is in co-codamol) with alcohol, especially regular drinking, significantly increases your risk of serious liver damage."

* Explain the Mechanism: "Both the alcohol and the paracetamol are processed by your liver. Regular drinking can make your liver more vulnerable to the toxic effects of paracetamol. It essentially depletes your liver's natural defences."

* Give Specific Advice: "The safest advice is to avoid alcohol completely while you are taking this medication. If you are a regular drinker, you should not exceed the recommended dose of paracetamol under any circumstances, and you must discuss your alcohol intake with your doctor or pharmacist."

Prescription Review & Mechanism of Action

Question 8: Drug Interaction Review

A prescription is written for a patient taking Simvastatin 40mg at night for high cholesterol. The GP now adds a course of Clarithromycin 500mg BD for a chest infection. Both drugs are metabolised by CYP3A4.

What is the problem, and what should the pharmacist do?

* Problem: Clarithromycin is a potent inhibitor of CYP3A4. This will dramatically decrease the metabolism of simvastatin, leading to a significant increase in simvastatin plasma levels.

* Risk: This greatly increases the risk of dose-related adverse effects, most notably severe statin-associated muscle symptoms (SAMS) or even rhabdomyolysis.

* Action: The pharmacist must contact the prescriber. The recommendation would be to either: 1) Temporarily withhold the simvastatin for the duration of the antibiotic course, or 2) Use a different antibiotic that does not inhibit CYP3A4. The patient should also be advised to report any unexplained muscle pain, tenderness, or weakness immediately.

Question 9: Mechanism of Action

Match the term to its correct description.

1. Prodrug | 2. Enzyme Induction | 3. First-Pass Metabolism | 4. Cytochrome P450

Descriptions:

A. A family of heme-containing enzymes critical for Phase 1 oxidation reactions.

B. A pharmacologically inactive compound that is converted in the body to an active drug.

C. Pre-systemic elimination of a drug after oral administration, reducing its bioavailability.

D. An increase in enzyme activity, leading to accelerated drug metabolism and reduced efficacy.

Answer:

* 1 - B

* 2 - D

* 3 - C

* 4 - A